A signal via the B7: CD28 costimulatory molecular family is deeply involved in activation, inhibition and adjustment of a T cell reaction. It has been known that a PD-1 (Programmed Death-1) molecule belonging to the B7: CD28 costimulatory molecular family reacts with PD-L1 and PD-L2, and negatively controls the T cell reaction (Non-Patent Document 1). At first, it has been suggested that PD-1 expressed on a T cell reacts with PD-L1 expressed on an antigen presenting cell or a cancer cell, or PD-L2 on an antigen presenting cell to inhibit the activation of the T cell.
On the other hand, it has been known that PD-L1 is also expressed on a T cell. Recently, a possibility that PD-L1 binds with not only PD-1 but also B7-1 (CD80), and PD-L1 present on a T cell sends a negative signal to the T cell has been demonstrated (Non-Patent Document 2). However, what physiological and pathological roles are played by PD-L1 expressed on a T cell, in an immune reaction, is entirely unknown. Regarding PD-L2, it has been only known so far that it is expressed on a dendritic cell, a macrophage, a B1B cell, and a mast cell derived from bone marrow only upon induction, and its expression on a T cell is not clear. Therefore, a role played by PD-L2, which is physiologically or forcibly expressed on a T cell, is not entirely known.
There has been demonstrated a possibility that an immune response inhibiting signal from a costimulatory molecule, a representative of which is CTLA4 or PD-1, induces tolerance (immunological tolerance) via suppression of priming or the effector function at the initial stage of an autoreactive T cell while balancing with an immune response activating signal from a costimulatory molecule, a representative of which is a T cell receptor (TCR) or CD28, thereby protecting tissues from the autoreactive T cell and, on the other hand, controlling infection immunity or tumor immunity. In addition, it has been thought that certain tumors or viruses suppress the activation and proliferation of a T cell by a direct or indirect mechanism utilizing the costimulatory molecule, to weaken an immune reaction against themselves. Further, it has been thought that in a part of diseases attributed to a functional disorder of a T cell, abnormality of the costimulatory molecule is a cause for a functional disorder of a T cell.